Proteome-wide chemotype profiling reveals the cysteinome as a pan-PTM hub

The functional diversity of the human proteome is largely defined by post-translational modifications (PTMs), yet systematic discovery of low-abundance or previously unknown modifications remains a challenge. Here, we apply an open-search mass spectrometry pipeline with multi-layered quality control to 49 human tissue and cell line datasets, generating a high-confidence resource of 141 chemotypes. Cysteine emerges as a pan-PTM hub, a residue that accommodates an exceptionally broad spectrum of PTM chemistries. Over half of all chemotypes occur on cysteine, and individual residues can carry up to 42 distinct modifications, forming complex crosstalks. Among these, we identify and characterize S-iminoglycation, a previously unknown modification arising from oxidative deamination of glycine. This modification is catalysed by amino acid oxidase, trapping the transient iminoglycine intermediate on cysteine thiols and directly coupling amino acid catabolism to protein function. Our findings reframe the cysteinome not merely as a redox switch but as an integrative chemical sponge that balances stochastic noise with regulated signalling, with particular enrichment in metabolic enzymes and secreted proteins. This work provides a broadly applicable discovery pipeline and reveals an unanticipated layer of chemical complexity that links metabolism, redox homeostasis and environmental exposure.